Method of Improving Treatments in Rheumatic and Arthritic Diseases

Abstract

Improved treatments of joint diseases, such as, e.g. osteoarthritis and rheumatoid arthritis, and pain, wherein a strontium-containing compound is administered alone or in combination with one or more second therapeutically and/or prophylactically active substances, selected from the group consisting of bisphosphonates, glucosamine, pallitative agents, analgesic agents, disease modifying anti-rheumatic compounds (DMARDs), selective estrogen receptor modulators (SERMs), aromatase inhibitors, non-steroidal anti-inflammatory agents (NSAIDs), COX-2 inhibitors, COX-3 inhibitors, opioids, inhibitors/antagonists of IL-1, inhibitors/antagonists of TNF-alpha, inhibitors of matrix metallo-proteinases (MMPs), cathepsin K inhibitors, inhibitors/antagonists of RANK-ligand, statins, glucocorticoids, chondroitin sulphate, NMDA receptor antagonists, inhibitors of interleukin-I converting enzyme, Calcitonin gene related peptide antagonists, glycine antagonists, vanilloid receptor antagonists, inhibitors of inducible nitric oxide synthetase (iNOS), N-acetylcholine receptor agonists, neurokinin antagonists, neuroleptic agents, PAR2 receptor antagonists and anabolic growth factors acting on joint tissue components. Pharmaceutical compositions comprising a strontium-containing compound and a second therapeutically and/or prophylactically active substance as defined above.

1 . A pharmaceutical composition comprising i) a strontium-containing compound as a first therapeutically and/or prophylactically active substance, and ii) a second therapeutically and/or prophylactically active substance selected from the group consisting of bisphosphonates, glucosamine, palliative agents, analgesic agents, disease modifying anti-rheumatic compounds (DMARDs), selective estrogen receptor modulators (SERMs), aromatase inhibitors, non-steroidal anti-inflammatory agents (NSAIDs), COX-2 inhibitors, COX-3 inhibitors, opioids, inhibitors/antagonists of IL-1, inhibitors/antagonists of TNF-α, inhibitors of matrix metallo-proteinases (MMPs), cathepsin K inhibitors, inhibitors/antagonists of RANK-ligand, statins, glucocorticoids, chondroitin sulphate, NMDA receptor antagonists, inhibitors of interleukin-I converting enzyme, Calcitonin gene related peptide antagonists, glycine antagonists, vanilloid receptor antagonists, inhibitors of inducible nitric oxide synthetase (iNOS), N-acetylcholine receptor agonists, neurokinin antagonists, neuroleptic agents, PAR2 receptor antagonists and anabolic growth factors acting on joint tissue components. 
   
   
       2 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is a bisphosphonate or a glucosamine. 
   
   
       3 . The pharmaceutical composition according to  claim 2 , wherein the second therapeutically and/or prophylactically active substance is a bisphosphonate selected from the group consisting of ibandronate, zoledronate, alendronate, risedronate, ethidronate, chlodronate, tiludronate, minodronate, incadronate, olpadronate and pamidronate. 
   
   
       4 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is glucosamine sulphate. 
   
   
       5 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is selected from the group consisting of heroin, fentanyl, morphine, oxycodone, hydrocodone, methadone, buprenorphine, pentazocine, butorphanol, dezocine, nalbuphine, meperidine, normeperidine, hydromorphone, codeine, levorphanol, tramadol, endorphin, nociceptin, endomorphin, and active metabolites thereof. 
   
   
       6 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is an NSAID selected from the group consisting of enolic acids, heteroaryl acetic acids; Indole and indene acetic acids; Para-amino phenol derivatives propionic acids; Sulphonanilides; fenamates; alkanones; pyrazolones, salicylates; paracetamol; or a pharmaceutically acceptable salt thereof. 
   
   
       7 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is a selective COX-2 inhibitor, that has a 10 fold higher affinity for the COX-2 isoenzyme compared to COX-1, the selective COX-2 inhibitor being rofecoxib (Vioxx), valdecoxib (Bextra), celecoxib (Celebrex), etoricoxib (Arcoxia), lumiracoxib (Prexige), parecoxib (Dynastat), deracoxib (Deram), tiracoxib, meloxicam, nimesolide, (1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6dimethyl-6H-dibenzo[b,d]pyran carboxylic acid (CT-3), 2(5H)-Furanone, 5,5-dimethyl (1-methylethoxy)[4(methylsulfonyl)phenyl]-(DFP); Carprofen (RIMADYLO), (Acetyloxy)-benzoic acid, 3-[(nitrooxy)methyl]phenyl ester (NCX4016), P54 (CAS Reg. No. 130996 0) 2,6-Bis(1,1-dimethylethyl) [(E)-(2-ethyl-1,1-dioxo isothiazolidinylidene)methyl]phenoI (S-2474), 5(R)-Thio sulfonamide-3(2H)-benzofuranone (SVT-2016) N-[3-(Formyl-amino)oxo phenoxy-4H benzopyran yl]methanesulfonamide (“T-614”); or a pharmaceutically acceptable salt thereof. 
   
   
       8 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is a DMARD selected from the group consisting of doxycycline, chondroitin sulfate, methotrexate, leflounomide (ARAVA®, Aventis), dimethylnitrosamine, azatriopine, hydroxychloroqine, cyclosporine, minocycline, salazopyrine, penicillamine, aurothiomalate (gold salt), cyclophosphamide, azathioprine and pharmacologically active metabolites thereof. 
   
   
       9 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is a selective estrogen receptor modulator selected from the group consisting of raloxifene, arzoxifene, droloxifene, tamoxifen, 4-hydroxy-tamoxifen, 4′-iodotamoxifen, toremifene, (deaminohydroxy)-toremifene, chlomiphene, levormeloxifene, ormeloxifene, chroman derivatives, coumarin derivatives, idoxifene, nafoxidine, TAT-59, LY-353381, CP-336156, MDL-103323, EM-800, ICI-182, ICI 183,780, ICI 164,384, ICI 183,780, ICI 164,384, diethylstilbesterol, genistein, nafoxidine, nitromifene, moxesterol, diphenol hydrochrysene, erythro-MEA, allenolic acid, equilin-3-sulphate, cyclophenyl, chlorotrianisene, ethamoxytriphetol, lasofoxifene, bazedoxifene, genistein, tibolone, ospemifene, tesmilifene, droloxifene, panomifene, zindoxifene, meproxifene, faslodex, and pharmacologically active metabolites of any of the listed substances. 
   
   
       10 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is selected from the group consisting of inhibitors of IL-1, a monoclonal antibody against IL-1 and soluble IL-1 receptor derivatives. 
   
   
       11 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is an inhibitor of interleukin-I converting enzyme (ICE). 
   
   
       12 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is an inhibitor of TNF-α. 
   
   
       13 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is selected from the group consisting of OPG and other inhibitors of RANK-ligand. 
   
   
       14 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is selected from the group consisting of inhibitors of a matrix metalloproteinase aggrecanase, cathepsin K and another protease involved in the catabolic processes of tissue destruction in joint diseases. 
   
   
       15 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is chondroitin sulphate or keratin sulphate. 
   
   
       16 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is hyaluronic acid. 
   
   
       17 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is a glucocorticoid. 
   
   
       18 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is an endothelin-1 antagonist/inhibitor. 
   
   
       19 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is an anabolic growth factor derived from bone or cartilage matrix proteins. 
   
   
       20 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is an anabolic growth factor. 
   
   
       21 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is a statin. 
   
   
       22 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is an aromatase inhibitor. 
   
   
       23 . The pharmaceutical composition according to  claim 1 , wherein the second therapeutically and/or prophylactically active substance is a sulphated cyclodextrin. 
   
   
       24 . The pharmaceutical composition according to  claim 1 , wherein the strontium-containing compound is selected from the group of organic strontium salts comprising: strontium malonate, strontium succinate, strontium fumarate, strontium ascorbate, strontium aspartate in either L and/or D-form, strontium glutamate in either L- and/or D-form, strontium pyruvate, strontium tartrate, strontium glutarate, strontium maleate, strontium methanesulfonate, strontium benzenesulfonate and strontium ranelate, strontium acetyl salicylate, strontium salicylate, strontium citrate, strontium alendronate, strontium risedronate, strontium chlodronate, strontium ethidronate and strontium L-threonate, strontium ibandronate, strontium ibuprofenate, strontium flubiprofenate, strontium ketoprofenate, strontium phorbol 12,13-didecanoate 20-homovanillate, strontium indomethacinate, strontium carprofenate, strontium naproxenate, strontium acetyloxy-benzoate, strontium 2-Iminopiperidine, strontium methotrexate, strontium salsalate and strontium sulfasalazinate. 
   
   
       25 . The pharmaceutical composition according to  claim 1 , wherein the strontium-containing compound and the second therapeutically and/or prophylactically active substance are present in a single composition. 
   
   
       26 . The pharmaceutical composition according to  claim 1 , wherein the strontium-containing compound and the second therapeutically and/or prophylactically active substance are present in a kit comprising a first and a second container, the first container comprising the strontium-containing compound and the second container comprising the second therapeutically and/or prophylactically active substance. 
   
   
       27 . The pharmaceutical composition according to  claim 26  further comprising instructions for simultaneous or sequential use of the first and the second therapeutically and/or prophylactically active substance. 
   
   
       28 . The pharmaceutical composition according to  claim 1  designed for oral administration. 
   
   
       29 - 39 . (canceled) 
   
   
       40 . A method for the treatment of a joint disease selected from the group consisting of OA and RA, the method comprising administering to a subject in need thereof an effective dose of a strontium-containing compound via the oral route. 
   
   
       41 . A method for the treatment of a joint disease selected from the group consisting of OA and RA, the method comprising administering to a subject in need thereof an effective dose of a strontium-containing compound via the oral route and an effective dose of a second therapeutically and/or prophylactically active substance selected from the group consisting of bisphosphonates, glucosamine, palliative agents, analgesic agents, disease modifying anti-rheumatic compounds (DMARDs), selective estrogen receptor modulators (SERMs), aromatase inhibitors, non-steroidal anti-inflammatory agents (NSAIDs), COX-2 inhibitors, COX-3 inhibitors, opioids, inhibitors/antagonists of IL-1, inhibitors/antagonists of TNF-α, inhibitors of matrix metallo-proteinases (MMPs), cathepsin K inhibitors, inhibitors/antagonists of RANK-ligand, statins, glucocorticoids, chondroitin sulphate, NMDA receptor antagonists, inhibitors of interleukin-I converting enzyme, Calcitonin gene related peptide antagonists, glycine antagonists, vanilloid receptor antagonists, inhibitors of inducible nitric oxide synthetase (iNOS), N-acetylcholine receptor agonists, neurokinin antagonists, neuroleptic agents, PAR2 receptor antagonists and anabolic growth factors acting on joint tissue components. 
   
   
       42 . A method for the treatment of a joint disease selected from the group consisting of OA and RA, the method comprising administering to a subject in need thereof an effective dose of a strontium-containing compound via the oral route and an effective dose of a second therapeutically and/or prophylactically active substance selected from the group consisting of palliative agents, analgesic agents and anti-inflammatory agents. 
   
   
       43 . (canceled) 
   
   
       44 . The method according to  claim 40 , wherein the strontium-containing compound is strontium malonate, strontium succinate, strontium fumarate, strontium ascorbate, strontium aspartate in either L and/or D-form, strontium glutamate in either L- and/or D-form, strontium pyruvate, strontium tartrate, strontium glutarate, strontium maleate, strontium methanesulfonate, strontium benzenesulfonate and strontium ranelate, strontium acetyl salicylate, strontium salicylate, strontium citrate, strontium alendronate, strontium risedronate, strontium chlodronate, strontium ethidronate and strontium L-threonate, strontium ibandronate, strontium ibuprofenate, strontium flubiprofenate, strontium ketoprofenate, strontium phorbol 12,13-didecanoate 20-homovanillate, strontium indomethacinate, strontium carprofenate, strontium naproxenate, strontium acetyloxy-benzoate, strontium 2-Iminopiperidine, strontium methotrexate, strontium salsalate or strontium sulfasalazinate. 
   
   
       45 . (canceled) 
   
   
       46 . The method according to  claim 41 , wherein the strontium-containing compound and the second therapeutically and/or prophylactically active substance are administered in the form of a single composition. 
   
   
       47 . The method according to  claim 41 , wherein the joint disease is OA and the subject is given a daily dose of ionic strontium corresponding to 100-2000 mg. 
   
   
       48 . The method according to  claim 41 , wherein the joint disease is RA and the subject is given a daily dose of ionic strontium corresponding to 100-2000 mg. 
   
   
       49 . The method according to  claim 41  where the strontium compound is given in a daily dose of ionic strontium corresponding to 100-2000 mg together with meloxicam administered in a daily dose of 5-20 mg. 
   
   
       50 . The method according to  claim 41  claims where the strontium compound is given in a daily dose of ionic strontium corresponding to 100-2000 mg together with piroxicam administered in a daily dose of 10-30 mg. 
   
   
       51 . The method according to  claim 41  where the strontium-containing compound is given in a daily dose of ionic strontium corresponding to 100-2000 mg together with naproxen administered in a daily dose of 500-1500 mg. 
   
   
       52 . The method according to  claim 41  where the strontium compound is given in a daily dose of ionic strontium corresponding to 100-2000 mg together with dexibuprofen administered in a daily dose of 500-1600 mg. 
   
   
       53 . The method according to  claim 41  where the strontium compound is given in a daily dose of ionic strontium corresponding to 100-2000 mg together with ibuprofen administered in a daily dose of 1000-3200 mg. 
   
   
       54 . The method according to  claim 41  where the strontium compound is given in a daily dose of ionic strontium corresponding to 100-2000 mg together with celecoxib administered in a daily dose of 100-200 mg. 
   
   
       55 . The method according to  claim 41  where the strontium compound is given in a daily dose of ionic strontium corresponding to 100-2000 mg together with salsalate administered in a daily dose of 1000-3000 mg. 
   
   
       56 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is an enolic acid which is piroxicam, tenoxicam, meloxicam, or a pharmaceutically acceptable salt thereof. 
   
   
       57 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is a heteroaryl acetic acid which is diclofenac, tolmetin, ketorolac, misoprostol, zomepirac, or a pharmaceutically acceptable salt thereof. 
   
   
       58 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is an indole or indene acetic acid which is indomethacin, mefenamic acid, sulindac, etodolac, or a pharmaceutically acceptable salt thereof. 
   
   
       59 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is a para-amino phenol derivative which is phenacetin, acetaminophen, or a pharmaceutically acceptable salt thereof. 
   
   
       60 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is a propionic acid which is naproxen, flurbiprofen, fenoprofen, oxaprozin, carprofen, ketoprofen, ibuprofen, or a pharmaceutically acceptable salt thereof. 
   
   
       61 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is Nimesulide or a pharmaceutically acceptable salt thereof. 
   
   
       62 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is a fenamate which is mefenamic acid, meclofenamate, flufenamic acid, or a pharmaceutically acceptable salt thereof. 
   
   
       63 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is nabumetome or a pharmaceutically acceptable salt thereof. 
   
   
       64 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is a pyrazolone which is phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, kebuzone, or a pharmaceutically acceptable salt thereof. 
   
   
       65 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is a salicylate which is acetyl salicylate (aspirin), salicylate, salsalate, difunisal, olsalazine, fendosal, sulfasalazine, thiosalicylate, or a pharmaceutically acceptable salt thereof. 
   
   
       66 . The pharmaceutical composition according to  claim 6 , wherein the second therapeutically and/or prophylactically active substance is paracetamol or a pharmaceutically acceptable salt thereof. 
   
   
       67 . The pharmaceutical composition according to  claim 10 , wherein the second therapeutically and/or prophylactically active substance is anakinra. 
   
   
       68 . The pharmaceutical composition according to  claim 10 , wherein the second therapeutically and/or prophylactically active substance is a soluble IL-1 receptor derivative modified by attachment of polyethylene glycol. 
   
   
       69 . The pharmaceutical composition according to  claim 11 , wherein the second therapeutically and/or prophylactically active substance is Pralnacasan. 
   
   
       70 . The pharmaceutical composition of  claim 12 , wherein the inhibitor of TNF-α is etanercept (Enbrel®), adalimumab (Humira®), or infliximab (Remicade®). 
   
   
       71 . The pharmaceutical composition of  claim 13 , wherein the inhibitor of RANK-ligand is monoclonal antibody AMG-162. 
   
   
       72 . The pharmaceutical composition according to  claim 14 , wherein the second therapeutically and/or prophylactically active substance is a matrix metalloproteinase inhibitor which is an inhibitor of MMP-1, MMP-13, or MMP-3. 
   
   
       73 . The pharmaceutical composition according to  claim 14 , wherein the second therapeutically and/or prophylactically active substance is an inhibitor of a protease involved in the catabolic processes of tissue destruction in joint diseases, wherein the joint disease is OA or RA. 
   
   
       74 . The pharmaceutical composition according to  claim 17 , wherein the glucocorticoid is prednisolone, prednisone, methylprednisolone, betamethasone, hydrocortisone, cortisone, triamcinolone, dexamethasone, beclomethasone, budesonide, deoxycortone or fludrocortisone. 
   
   
       75 . The pharmaceutical composition according to  claim 19 , wherein the second therapeutically and/or prophylactically active substance is a segment of or fragment from collagen type I, collagen type II, collagen type IX, collagen type XI, bone sialo protein (BSP), osteonection, osteopontin, osteocalcin (also known as bone GLA protein), cartilage oligomeric matrix protein (COMP), cartilage intermediate layer protein (CILP) or aggrecan. 
   
   
       76 . The pharmaceutical composition according to  claim 20 , wherein the anabolic growth factor is human growth hormone (hGH), parathyroid hormone (PTH), glucagon like peptide-2 (GLP-2), or insulin like growth factor-1 (IGF-1) with or without IGF binding protein 3 (IGFBP-3). 
   
   
       77 . The pharmaceutical composition according to  claim 21 , wherein the statin is nystatin, pravastatin, fluvostatin, atorvastatin and cerivastatin or a therapeutically active derivative thereof. 
   
   
       78 . The method of  claim 40 , wherein the subject is a human. 
   
   
       79 . The method of  claim 41 , wherein the subject is a human. 
   
   
       80 . The method of  claim 42 , wherein the subject is a human. 
   
   
       81 . The method according to  claim 41 , wherein the strontium-containing compound is strontium malonate, strontium succinate, strontium fumarate, strontium ascorbate, strontium aspartate in either L and/or D-form, strontium glutamate in either L- and/or D-form, strontium pyruvate, strontium tartrate, strontium glutarate, strontium maleate, strontium methanesulfonate, strontium benzenesulfonate and strontium ranelate, strontium acetyl salicylate, strontium salicylate, strontium citrate, strontium alendronate, strontium risedronate, strontium chlodronate, strontium ethidronate and strontium L-threonate, strontium ibandronate, strontium ibuprofenate, strontium flubiprofenate, strontium ketoprofenate, strontium phorbol 12,13-didecanoate 20-homovanillate, strontium indomethacinate, strontium carprofenate, strontium naproxenate, strontium acetyloxy-benzoate, strontium 2-Iminopiperidine, strontium methotrexate, strontium salsalate or strontium sulfasalazinate. 
   
   
       82 . The method according to  claim 42 , wherein the strontium-containing compound is strontium malonate, strontium succinate, strontium fumarate, strontium ascorbate, strontium aspartate in either L and/or D-form, strontium glutamate in either L- and/or D-form, strontium pyruvate, strontium tartrate, strontium glutarate, strontium maleate, strontium methanesulfonate, strontium benzenesulfonate and strontium ranelate, strontium acetyl salicylate, strontium salicylate, strontium citrate, strontium alendronate, strontium risedronate, strontium chlodronate, strontium ethidronate and strontium L-threonate, strontium ibandronate, strontium ibuprofenate, strontium flubiprofenate, strontium ketoprofenate, strontium phorbol 12,13-didecanoate 20-homovanillate, strontium indomethacinate, strontium carprofenate, strontium naproxenate, strontium acetyloxy-benzoate, strontium 2-Iminopiperidine, strontium methotrexate, strontium salsalate or strontium sulfasalazinate.